WH25244

WH25244 is a novel proteolysis targeting chimera (PROTAC) designed to selectively degrade the anti-apoptotic proteins BCL-XL and mutant or hyperphosphorylated BCL2 in cancer cells, particularly chronic lymphocytic leukemia (CLL). It was developed to address resistance mechanisms that arise in CLL patients relapsing after treatment with BTK inhibitors and venetoclax. Unlike traditional BCL-2/BCL-XL inhibitors such as navitoclax, WH25244 links a navitoclax-derived ligand to a VHL E3 ligase ligand, enabling targeted degradation of both BCL-XL and mutant forms of BCL2. This dual-targeting approach overcomes multiple mechanisms of venetoclax resistance—including those driven by mutations in BTK, PLCG2, TP53, or stromal support—while minimizing platelet toxicity due to low VHL expression in platelets. Preclinical studies demonstrate that WH25244 induces apoptosis in both treatment-naïve and venetoclax-resistant CLL cells with superior potency compared to venetoclax or navitoclax and shows a favorable safety profile in vitro[1][2][4][5][6][9].